Novel Prognostic and Predictive Markers for Canine Mast Cell Tumours

Abstract

Mast cell tumours (MCTs) are the most common skin tumour of the dog, representing approximately 21% of all cutaneous tumours. Accurately predicting behaviour is critical in directing patient therapy, especially in canine MCTs as they range from benign to a fatal systemic disease. Grading is useful for prognosis, but it cannot predict the behaviour of each MCT. We hypothesized that biomarker staining in tumour tissues will correlate with patient outcome. A clinically annotated tissue microarray of primary, recurrent, and metastatic cutaneous canine MCTs (with and without adjunctive treatment) was created and high-throughput immunohistochemical staining profiling of 244 tumours from 189 dogs was performed. Total staining of KIT, a receptor tyrosine kinase that is an important driver of MCTs, was not prognostic. Mast cell tryptase levels were found to be prognostic in low-grade MCTs, with low tryptase-expressing tumours having a decreased time to recurrence and/or metastasis compared to high-tryptase expressing tumours. Two other proteins involved in protein degradation pathways were also investigated: c-CBL, an E3 ubiquitin ligase that also functions as an adaptor protein to regulate signaling pathways, and beclin-1, an autophagy protein. High c-CBL expressing tumours had a decreased MCT-related survival time in primary, adjunctive therapy treated, subcutaneous MCTs. Beclin-1 staining level was a strong predictive biomarker for cutaneous MCTs. High beclin-1 expressing tumours showed poor response to adjunctive treatment compared to low beclin-1 expressing tumours, especially for high-grade or high mitotic count tumours. These findings will hopefully improve our ability to prognosticate MCTs and help decide whether to pursue adjunctive treatment. Importantly, this is the first evidence that autophagy inhibitors may be useful in improving response to treatment for dogs with high-grade MCTs.